Tuning Side Arm Electronics in Unsymmetrical Cyclotriazadisulfonamide (CADA) Endoplasmic Reticulum (ER) Translocation Inhibitors to Improve their Human Cluster of Differentiation 4 (CD4) Receptor Down-Modulating Potencies

Cyclotriazadisulfonamide
prevents HIV entry into cells by down-modulating surface CD4 receptor
expression through binding to the CD4 signal peptide. According to
a two-site binding model, 28 new unsymmetrical analogues bearing a
benzyl tail group and nine bearing a cyclohexylmethyl tail have been
designed and synthesized. The most potent new CD4 down-modulator (40 (CK147); IC50 63 nM) has a 4-dimethylaminobenzenesulfonyl
side arm. One of the two side arms was varied with substituents in
different positions. This gave a range of CD4 down-modulation potencies
that correlated well with anti-HIV-1 activities. The side arms of
21 of the new benzyl-tailed analogues were modeled by means of quantum
mechanical calculations. For CADA analogues with arenesulfonamide
side arms, the pIC50 values for CD4 down-modulation correlated
with the component of the electric dipole moment in the aromatic ring,
suggesting that an attractive electronic interaction is a major factor
determining the stability of the complex between the molecule and
its target.